Submissions for variant NM_000162.5(GCK):c.601G>T (p.Ala201Ser)

dbSNP: rs794727775

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003883139	SCV004697928	pathogenic	Monogenic diabetes	2024-02-23	reviewed by expert panel	curation	The c.601G>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to serine at codon 201 (p.(Ala201Ser)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.929, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in four unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with seven informative meioses in one family (PP1_Strong; internal lab contributors). In summary, c.605T>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PS4_Moderate, PP1_Strong, PP4_Moderate.
Eurofins Ntd Llc (ga)	RCV000711778	SCV000231485	uncertain significance	not provided	2014-10-06	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000711778	SCV000842174	uncertain significance	not provided	2019-05-14	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002272161	SCV002556495	likely pathogenic	Maturity-onset diabetes of the young type 2	2020-12-31	criteria provided, single submitter	clinical testing	PM2, PP3, PM1, PP5
Ambry Genetics	RCV002354464	SCV002657638	uncertain significance	Maturity onset diabetes mellitus in young	2023-03-20	criteria provided, single submitter	clinical testing	The p.A201S variant (also known as c.601G>T), located in coding exon 6 of the GCK gene, results from a G to T substitution at nucleotide position 601. The alanine at codon 201 is replaced by serine, an amino acid with similar properties. This variant has been reported in association with maturity-onset diabetes of the young (MODY) (Osbak KK et al. Hum Mutat, 2009 Nov;30:1512-26). It was also reported in four individuals with suspicion of MODY and nine relatives; however, additional information was not provided (Mirshahi UL et al. Am J Hum Genet, 2022 Nov;109:2018-2028). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000711778	SCV003439932	likely pathogenic	not provided	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 201 of the GCK protein (p.Ala201Ser). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala201 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 25555642), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GCK protein function. ClinVar contains an entry for this variant (Variation ID: 198050). This missense change has been observed in individuals with clinical features of maturity onset diabetes of the young (PMID: 19790256, 25555642, 33046911; Invitae). This variant is not present in population databases (gnomAD no frequency).
GeneDx	RCV000711778	SCV005332766	pathogenic	not provided	2024-03-22	criteria provided, single submitter	clinical testing	Classified pathogenic by the ClinGen Monogenic Diabetes Expert Panel (ClinVar SCV004697928.1); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33046911, 25555642, 36257325, 19790256)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000711778	SCV005875513	likely pathogenic	not provided	2024-06-04	criteria provided, single submitter	clinical testing	The GCK c.601G>T; p.Ala201Ser variant (rs794727775, ClinVar Variation ID: 198050), is reported in the literature in cohorts with suspected maturity-onset diabetes of the young (Bennett 2015, Bonnefond 2020, Mirshahi 2022, Osbak 2009). Additionally, this variant is reported in four individuals affected with hyperglycemia and was found to segregate with disease in seven meiosis in a single family (Monogenic Diabetes Variant Curation Expert Panel). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.929). Based on available information, this variant is considered to be likely pathogenic. References: Link to Clinical Genome Resource Monogenic Diabetes Variant Curation Expert Panel: https://erepo.genome.network/evrepo/ui/classification/e88a1f47-bc1b-4f78-bda7-6d240f568d62 Bennett JT et al. Molecular genetic testing of patients with monogenic diabetes and hyperinsulinism. Mol Genet Metab. 2015 Mar;114(3):451-8. PMID: 25555642. Bonnefond A et al. Pathogenic variants in actionable MODY genes are associated with type 2 diabetes. Nat Metab. 2020 Oct;2(10):1126-1134. PMID: 33046911. Mirshahi UL et al. Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. Am J Hum Genet. 2022 Nov 3;109(11):2018-2028. PMID: 36257325. Osbak KK et al. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat. 2009 Nov;30(11):1512-26. PMID: 19790256.